PROCESSES FOR PREPARING MORPHINAN-6-ONE PRODUCTS WITH LOW LEVELS OF a,ß-UNSATURATED KETONE COMPOUNDS

ABSTRACT

The present invention generally relates to processes for preparing highly pure morphinan-6-one products. The processes involve reducing the concentration of alpha, beta unsaturated ketone compounds present as impurities in morphinan 6 one products or reaction mixtures including morphinan 6 one compounds by treatment with a sulfur-containing compound.

FIELD OF THE INVENTION

The present invention generally relates to processes for preparingmorphinan-6-one products. The processes involve reducing theconcentration of α,β-unsaturated ketone compounds from reaction mixturesincluding morphinan-6-one compounds.

BACKGROUND OF THE INVENTION

The morphinan alkaloids represent a family of structurally-relatedproducts of great medicinal importance. Particular morphinan compoundsof pharmaceutical relevance include, for example, codeine, hydrocodone,hydromorphone, morphine, nalbuphine, nalmefene, naloxone, naltrexone,oxycodone, and oxymorphone. Generally, these compounds are analgesics,which are used extensively for pain relief in the field of medicine dueto their action as opiate receptor agonists. However, nalmefene,naloxone, naltrexone, and naltrexone methyl bromide are opiate receptorantagonists, and are used for reversal of narcotic/respiratorydepression due to opiate receptor agonists, as addiction therapies, andto reverse other undesirable side effects of opiate agonist use, such assevere constipation.

Morphinan compounds and analogs thereof typically have a ring structuregenerally corresponding to Formula (1):

Various methods are known for the synthesis of morphinan compoundscorresponding to Formula (1). Conventional methods used in thecommercial production of morphinan compounds typically involve theextraction of opium alkaloids from poppies (Papaver somniferum).Generally speaking, these processes involve the extraction of thealkaloids from opium in a liquid, precipitation of the alkaloids,separation of the raw alkaloids (e.g., morphine and secondary alkaloidssuch as papaverine, codeine, and thebaine), and purification of thevarious alkaloids, optionally followed by semi-synthesis steps toproduce particular morphinan compounds. See, for example, Barbier, A.,“The Extraction of Opium, Twenty-five years of commercial experience inthe treatment of opium,” Ann. Pharm. Franc., 1947, 5, 121-40; Barbier,A., “The Extraction of Opium Alkaloids,” Bull. Narcotics, 1950, vol. 3,22-29; Neumann, W, “The Manufacture of Alkaloids from Opium,” Bull.Narcotics, 1957, vol. 2, 34-40; Lednicer and Mitscher, Organic Chemistryof Drug Synthesis, chapter 15, (Wiley 1977); French Patent No. 1,000,543to Penau et al.; British Patent No. 713,689 to Wood et al.; and U.S.Pat. No. 2,009,181 to Kábay.

Synthetic methods for producing various morphinan compounds are alsoknown. These methods commonly utilize 3-methoxy-phenylethylamine as astarting material and include a Grewe cyclization step. For example, inU.S. Pat. No. 4,368,326, Rice discloses a process for preparing anordihydrothebainone (e.g., 1-bromo-N-formylnordihydrothebainone) from aβ,γ-hexahydroisoquinolone (e.g.,1-(2′-bromo-4′-methoxy-5′-hydroxybenzyl)-2formyl-1,3,4,5,7,8-hexahydroquinolin-6-one)by Grewe cyclization catalyzed using a super acid catalyst alone or witha combination of an ammonium fluoride complex andtrifluoromethanesulfonic acid.

Many pharmaceutically desirable morphinan compounds and analogs thereofhave a ketone group on the C-ring of Formula (1) and a saturated bondbetween the two carbon atoms positioned α and β to the ketone on theC-ring of Formula (1). According to the common nomenclature, the ketoneis present on the C(6) carbon atom, with the α and β carbon atoms beingthe C(7) and C(8) positions (see, e.g., Formula (1)). Thus, thesecompounds may be referred to as morphinan-6-one compounds. Variousprocesses for producing morphinan-6-one compounds are known, many ofwhich involve some form of catalytic hydrogenation of α,β-unsaturatedketone intermediate compounds at particular points in the process.Commonly used catalysts include, for example, palladium and platinum.For example, in U.S. Pat. No. 6,177,567 to Chiu et al.,14-hydroxycodeinone (an α,β-unsaturated ketone compound) is converted tooxycodone by hydrogenating the α,β-unsaturation using conventionalmethods such as reduction by diphenylsilane and Pd(Ph₃P)/ZnCl₂, or withsodium hypophosphite in conjunction with a Pd/C catalyst in aqueousacetic acid, or by Pd/C catalytic transfer hydrogenation.

While these and other methods of reducing or removing theα,β-unsaturation are generally effective, α,β-unsaturated ketonecompounds may persist as impurities in the final products of desirablyα,β-saturated morphinan-6-one products, such as oxycodone. Additionally,known hydrogenation methods may tend to undesirably reduce the ketone aswell as reducing or removing the α,β-unsaturation. Further, these andother hydrogenation methods are not normally capable of efficiently andeconomically reducing the levels of 7,8-unsaturation to below 10 to 100parts per million, or less.

Some α,β-unsaturated ketone compounds show mutagenic activity in certaintests. Therefore, a need persists for processes for preparing highlypure morphinan-6-one products having a relatively low concentration ofα,β-unsaturated ketone compounds present as impurities therein.

SUMMARY OF THE INVENTION

Among the various aspects of the present invention is the provision of aprocess for the preparation of morphinan-6-one products. The processinvolves reducing the concentration of α,β-unsaturated ketone compoundswhich are present as impurities in reaction mixtures includingmorphinan-6-one compounds. The process generally involves forming areaction mixture including a morphinan-6-one compound and anα,β-unsaturated ketone compound and treating the reaction mixture with asulfur-containing compound. In one embodiment, the sulfur-containingcompound is a sulfur-containing inorganic acid or salt thereof.

Briefly, therefore, the present invention is directed to a process forthe preparation of a morphinan-6-one product, the process comprising:

forming a reaction mixture comprising a morphinan-6-one compound and anα,β-unsaturated ketone compound;

treating the reaction mixture with a sulfur-containing compound toreduce the concentration of the α,β-unsaturated ketone compound in thereaction mixture; and

recovering the morphinan-6-one compound to produce the morphinan-6-oneproduct;

wherein

the morphinan-6-one compound corresponds to Formula (2):

the α,β-unsaturated ketone compound corresponds to Formula (3):

X is —N(R₁₇)— or —N⁺(R_(17a)R_(17b))—;

R₁ and R₂ are independently selected from hydrogen, substituted andunsubstituted acyl, acyloxy, alkenyl, alkoxy, alkoxyaryl, alkyl,alkylamino, alkylthio, alkynyl, amino, aryl, arylalkoxy, carboalkoxy,carbonyl, carboxyalkenyl, carboxyalkyl, carboxyl, cyano, cyanoalkyl,cycloalkyl, cycloalkylalkyl, cycloalkylether, halo, haloalkoxy,haloalkyl, heteroaryl, heterocyclic, hydroxyalkyl, hydroxyl, or nitro;

R₃ is hydrogen, hydroxy, protected hydroxy, alkoxy, or acyloxy;

R₁₀ is hydrogen, hydroxy, protected hydroxy, halo, keto, tosyl, mesyl,or trifluoromesyl;

R₁₄ is hydrogen, hydroxy, or protected hydroxy;

R₁₇ is hydrogen, alkyl, cycloalkyl, alkylcarboxy, alkylenecycloalkyl,alkoxycarbonyl, allyl, alkenyl, acyl, aryl, formyl, formyl ester,formamide, benzyl, or an amino protecting group; and

R_(17a) and R_(17b) are independently selected from hydrogen, alkyl,alkenyl, allyl, cycloalkyl, aryl, or benzylyl, and

the morphinan-6-one compound comprises less than about 0.1% (by weight)morphinan-6-one product of the α,β-unsaturated ketone compound.

The present invention is also directed to a process for preparing amorphinan-6-one product, the process comprising:

forming a reaction mixture comprising an α,β-unsaturated ketonecompound;

treating the reaction mixture with a sulfur-containing compound toreduce the α,β-unsaturated ketone compound to form a morphinan-6-onecompound; and

recovering the morphinan-6-one compound to form the morphinan-6-oneproduct,

wherein

the morphinan-6-one compound corresponds to Formula (2):

the α,β-unsaturated ketone compound corresponds to Formula (3):

X is —N(R₁₇)— or —N⁺(R_(17a)R_(17b))—;

R₁ and R₂ are independently selected from hydrogen, substituted andunsubstituted acyl, acyloxy, alkenyl, alkoxy, alkoxyaryl, alkyl,alkylamino, alkylthio, alkynyl, amino, aryl, arylalkoxy, carboalkoxy,carbonyl, carboxyalkenyl, carboxyalkyl, carboxyl, cyano, cyanoalkyl,cycloalkyl, cycloalkylalkyl, cycloalkylether, halo, haloalkoxy,haloalkyl, heteroaryl, heterocyclic, hydroxyalkyl, hydroxyl, or nitro;

R₃ is hydrogen, hydroxy, protected hydroxy, alkoxy, or acyloxy;

R₁₀ is hydrogen, hydroxy, protected hydroxy, halo, keto, tosyl, mesyl,or trifluoromesyl;

R₁₄ is hydrogen, hydroxy, or protected hydroxy;

R₁₇ is hydrogen, alkyl, cycloalkyl, alkylcarboxy, alkylenecycloalkyl,alkoxycarbonyl, allyl, alkenyl, acyl, aryl, formyl, formyl ester,formamide, benzyl, or an amino protecting group; and

R_(17a) and R_(17b) are independently selected from hydrogen, alkyl,alkenyl, allyl, cycloalkyl, aryl, or benzylyl.

Other objects and features will be in part apparent and in part pointedout hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is generally directed to processes for preparinghighly pure morphinan-6-one products. The processes generally involvetreating a reaction mixture including a morphinan-6-one compound and anα,β-unsaturated ketone compound with a sulfur-containing compound.Advantageously, the process effectively reduces the concentration ofundesirable α,β-unsaturated ketone compounds to acceptable levelswithout removing or otherwise affecting other more desirable compoundsor substituent groups or unsaturation thereon. Moreover, thesulfur-containing compound may be utilized to reduce the concentrationof α,β-unsaturated ketone compounds present in the reaction mixture fromlevels of about 0.5% (by weight) or more to levels of not more thanabout 0.1% (by weight), or lower (e.g., about 0.01% (by weight), about0.001% (by weight), or lower), with minimal side reactions, ketonereduction, and/or any other undesirable effects.

Morphinan Products and Processes for Preparing the Same

Generally speaking, the morphinan-6-one products of interest in theprocess of the present invention include morphinan compounds having aketo group at the C(6) carbon atom on the C-ring and a saturated bondbetween the C(7) and C(8) carbon atoms on the C-ring (i.e.,morphinan-6-one compounds). More specifically, the morphinan-6-onecompounds are opiate receptor agonists or antagonists generallycorresponding to Formula (2):

wherein

X is —N(R₁₇)— or —N⁺(R_(17a)R_(17b))—;

R₁ and R₂ are independently selected from hydrogen, substituted andunsubstituted acyl, acyloxy, alkenyl, alkoxy, alkoxyaryl, alkyl,alkylamino, alkylthio, alkynyl, amino, aryl, arylalkoxy, carboalkoxy,carbonyl, carboxyalkenyl, carboxyalkyl, carboxyl, cyano, cyanoalkyl,cycloalkyl, cycloalkylalkyl, cycloalkylether, halo, haloalkoxy,haloalkyl, heteroaryl, heterocyclic, hydroxyalkyl, hydroxyl, or nitro;

R₃ is hydrogen, hydroxy, protected hydroxy, alkoxy, or acyloxy;

R₁₀ is hydrogen, hydroxy, protected hydroxy, halo, keto, tosyl, mesyl,or trifluoromesyl;

R₁₄ is hydrogen, hydroxy, or protected hydroxy;

R₁₇ is hydrogen, alkyl, cycloalkyl, alkylcarboxy, alkylenecycloalkyl,alkoxycarbonyl, allyl, alkenyl, acyl, aryl, formyl, formyl ester,formamide, benzyl, or an amino protecting group; and

R_(17a) and R_(17b) are independently selected from hydrogen, alkyl,alkenyl, allyl, cycloalkyl, aryl, or benzyl.

When R₁₇ is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, or benzyl, saltsof the secondary or tertiary amine can be formed wherein the anion ischloride, bromide, acetate, formate, sulfate, bisulfate, bisulfite,oxalate, citrate, malate, tartrate, triflate, trifluoroacetate, methanesulfonate, and the like. When X is —N⁺(R_(17a)R_(17b))—, the counter-ioncan be chloride, bromide, iodide, trifluoroacetate,trifluoromethanesulfonate, methane sulfonate, acetate,p-toluenesulfonate, sulfate, bisulfate, bisulfite, phosphate, hydrogenphosphate, dihydrogen phosphate, fumarate, oxalate, formate, tartrate,benzoate, and the like.

In one preferred embodiment, R₁₄ is hydroxy or protected hydroxy. Inanother preferred embodiment, R₁₄ is hydrogen.

In either of the embodiments described above (i.e., when R₁₄ is hydroxyor protected hydroxy or R₁₄ is hydrogen), R₃ is either alkoxy, hydroxy,or protected hydroxy. In one particular embodiment, R₃ is methoxy.

In any one of the embodiments described above, X is —N(R₁₇)— or—N⁺(R_(17a)R_(17b))—, wherein R₁₇, R_(17a), and R_(17b) are defined asabove. Where X is —N(R₁₇)—, in one particularly preferred embodiment R₁₇is hydrogen, alkyl, alkenyl, alkylcarboxy, or cycloalkyl. Where X is—N⁺(R_(17a)R_(17b))—, in one particularly preferred embodiment R_(17a)and R_(17b) are independently hydrogen, alkyl, alkenyl, or cycloalkyl.

Representative morphinan-6-one compounds corresponding to Formula (2)(and the various preferred substituent group definitions describedabove) which can be treated according to the process described hereininclude, for example, oxymorphone, naloxone, naltrexone, naltrexonemethylbromide, nalbuphone, noroxymorphone, hydromorphone, hydrocodone,oxycodone, diethoxycarbonyl-noroxymorphone, salts thereof, and the like.Additionally, derivatives of the above morphinan-6-one compounds whichcan be treated according to the process described herein include, forexample, N-demethylated-, 10-hydroxy-, 10-halo, and10-keto-morphinan-6-one derivatives, their protected analogs, and thelike.

The method of producing the above-described morphinan-6-one compoundsfor use in the present invention is not narrowly critical, and variousmethods for producing morphinan-6-one compounds are well known in theart. For example, commercial processing methods for producing morphinancompounds typically involve the extraction of an opium alkaloid (e.g.,thebaine) from poppies, followed by various conventional precipitationand purification steps known to those of skill in the art. By way offurther example, the morphinan-6-one compound oxycodone may be producedfrom thebaine in a substantially two-step process, as illustrated inReaction Scheme 1:

Alternatively, various synthetic methods for producing theabove-described morphinan-6-one compounds are also known. In thesesynthetic methods, a Grewe cyclization reaction is commonly used to formnordihydrothebainone products such as by the processes described in U.S.Pat. Nos. 4,368,326, 4,410,700, 4,521,601, 4,556,712, 4,613,668,4,727,146, the entire disclosures of which are hereby incorporated byreference herein. Additionally, various methods useful for thesemi-synthesis of morphinan compounds and intermediates are known. Forexample, U.S. Pat. No. 6,177,567 to Chiu et al. and U.S. Pat. No.6,008,355 to Huang et al. (each of which is hereby incorporated byreference herein) describe methods for the synthesis of oxycodone fromcodeine. These and other conventional practices are generally applicablein carrying out the preparation of morphinan-6-one compounds andα,β-unsaturated ketone compounds that may be treated according to theprocesses described herein.

As noted above, in the various conventional processes for producingmorphinan-6-one compounds described above, the resulting morphinanproduct typically also includes some amount of an α,β-unsaturated ketonecompound present as an impurity in addition to the desiredmorphinan-6-one compound. The α,β-unsaturated ketone compounds presentas impurities generally correspond to Formula (3):

wherein X, R₁, R₂, R₃, R₁₀, and R₁₄ are defined as above.

Reaction Conditions

As noted above, the morphinan products produced from conventionalprocesses for preparing morphinan-6-one compounds also yield some amountof an α,β-unsaturated ketone present as an impurity; that is, both themorphinan-6-one compound corresponding to Formula (2) and theα,β-unsaturated ketone compound corresponding to Formula (3) are presentin the morphinan product.

The morphinan products produced from conventional morphinan processingmethods typically comprise less than about 2% by weight of anα,β-unsaturated ketone compound. Preferably, the morphinan productscomprise less than about 1% by weight of an α,β-unsaturated ketonecompound. More preferably, the morphinan products comprise less thanabout 0.8% by weight of an α,β-unsaturated ketone compound. Still morepreferably, the morphinan products comprise less than about 0.5% byweight of an α,β-unsaturated ketone compound. As noted above, however,it is desirable to minimize or further minimize the concentration ofα,β-unsaturated ketone compounds present in such products.

According to the present invention, a reaction mixture is formedincluding a morphinan-6-one compound of Formula (2) and anα,β-unsaturated ketone compound of Formula (3). The morphinan-6-onecompound and the α,β-unsaturated ketone compound may be produced by anyconventional method (such as those described above), and themorphinan-6-one compound may exist as the free base or as a salt, suchas the hydrochloride salt. The reaction mixture is treated with asulfur-containing compound to reduce the concentration of theα,β-unsaturated ketone compound (either by forming additionalmorphinan-6-one compound or by facilitating the removal of theα,β-unsaturated ketone compound), and the morphinan-6-one compound isrecovered to produce the desired morphinan-6-one product. This processis generically illustrated in Reaction Scheme 2, wherein the reactionmixture including the morphinan-6-one compound and the α,β-unsaturatedketone compound is shown in brackets, and X, R₁, R₂, R₃, R₁₀, and R₁₄are defined as above.

Various reaction mixtures (bracketed) including a morphinan-6-onecompound and an α,β-unsaturated ketone compound may be treated accordingto the processes described herein to yield various highly puremorphinan-6-one products, as illustrated in Reaction Schemes 3-10.

According to various embodiments, the reaction mixture is formed bydissolving or otherwise dispersing the morphinan-6-one compound and theα,β-unsaturated ketone compound in a media material (i.e., a morphinanproduct including the morphinan-6-one compound and the α,β-unsaturatedketone compound is dispersed in the media material). The reactionmixture is then treated with a sulfur-containing compound. Ideally, themorphinan-6-one compound and the α,β-unsaturated ketone compound are insolution, but a heterogeneous mixture may also be treated according tothe processes described herein.

The media material is desirably an aqueous media or an aqueous/organicsolvent biphasic media. Exemplary aqueous media for use in the processof the present invention includes, for example, water, water/alcoholmixtures, dilute inorganic solvents such as dilute sulfuric acid,ethereal solvents such as dioxane or tetrahydrofuran, combinationsthereof, and the like. Exemplary organic solvents for use inaqueous/organic solvent biphasic media includes, for example, butanone,ethyl acetate, butanol, diethyl ether, benzene, chloroform,tetrachloroethylene, toluene, 1,1,1-trichloroethane, carbontetrachloride, dibutyl ether, cyclohexane, hexane, dipentyl ether,heptane, hexadecane, combinations thereof, and the like.

Generally, a sufficient amount of media material to substantiallysolubilize the morphinan-6-one compound and the α,β-unsaturated ketonecompound in the reaction mixture is desired, Higher amounts of mediamaterial may increase the costs of manufacturing, as the more dilutereaction mixture may require additional process cycle time, or requirethe removal or excess media material during subsequent processing steps.

The weight ratio of media material to morphinan-6-one compound in thereaction mixture is preferably from about 1:1 to about 50:1. Morepreferably, the weight ratio of media material to morphinan-6-onecompound in the reaction mixture is from about 1:1 to about 25:1. Forexample, the weight ratio of media material to morphinan-6-one compoundin the reaction mixture may be from about 1:1 to about 5:1, from about1:1 to about 10:1, from about 1:1 to about 15:1, or from about 1:1 toabout 20:1. Still more preferably, the weight ratio of media material tomorphinan-6-one compound in the reaction mixture is from about 5:1 toabout 25:1. For example, the weight ratio of media material tomorphinan-6-one compound in the reaction mixture may be from about 5:1to about 10:1, from about 5:1 to about 15:1, or from about 5:1 to about20:1. Still more preferably, the weight ratio of media material tomorphinan-6-one compound in the reaction mixture is from about 5:1 toabout 15:1. For example, the weight ratio of media material tomorphinan-6-one compound in the reaction mixture may be from about 5:1to about 6:1, from about 5:1 to about 7:1, from about 5:1 to about 8:1,from about 5:1 to about 9:1, from about 5:1 to about 10:1, from about5:1 to about 11:1, from about 5:1 to about 12:1, from about 5:1 to about13:1, or from about 5:1 to about 14:1. Most preferably, the weight ratioof media material to morphinan-6-one compound in the reaction mixture isfrom about 5:1 to about 11:1. It will be understood that some portion ofthe media material may be derived from the sulfur-containing compounditself (e.g., as water of hydration).

Optionally, a phase transfer catalyst may also be added to theaqueous/organic solvent biphasic media. The phase transfer catalyst ispreferably any suitable composition for use in the transfer of reactants(i.e., morphinan-6-one compounds, α,β-unsaturated ketone compounds,and/or sulfur-containing compounds) between the aqueous and organicsolvent interface. Typically, the phase transfer catalyst is anammonium-based compound, such as a quaternary ammonium salt. Suitablequaternary ammonium salts for use as phase transfer catalysts includetetraalkylammonium salts such as, for example, tetramethyl-,tetraethyl-, tetrabutyl-, tetrahexyl-, tetraoctyl-, methyltriphenyl-,methyltrioctyl-, benzyltrimethyl-, benzyltriethyl-, benzyltributyl-,hexadecyltrimethyl-ammonium salts, and the like. Suitable salts include,for example, halide, hydroxide, bicarbonate, bisulfate, thiocyanate,tetrafluoroborate, and the like. Other phase transfer catalysts such asphosphonium salts may be suitable as well.

A variety of sulfur-containing compounds may be utilized to treat thereaction mixture and reduce the concentration of the α,β-unsaturatedketone compound according to the processes described herein. In variousembodiments, the sulfur-containing compound is a sulfur-containingnucleophile. As utilized herein, “nucleophile” refers to an ion ormolecule that donates a pair of electrons to an atomic nucleus to form acovalent bond. In other embodiments, the sulfur-containing compound is asulfur-containing reducing agent. As utilized herein, “reducing agent”refers to an agent having the ability to add one or more electrons to anatom, ion or molecule. In either of the two embodiments described above(i.e., when the sulfur-containing compound is a sulfur-containingnucleophile or a sulfur-containing reducing agent), thesulfur-containing compound is a compound having the ability to effectthe reduction of and/or a 1,4 addition across the α,β-unsaturated bondof the α,β-unsaturated ketone compound.

In one embodiment, the sulfur-containing compound is a sulfur-containinginorganic acid or salt thereof. Suitable sulfur-containing inorganicacids include, for example, hydrosulfuric acid (H₂S); sulfurous acid(H₂SO₃); persulfuric acid (H₂SO₅); thiosulfurous acid (H₂S₂O₂);dithionous acid (H₂S₂O₄); disulfurous acid (H₂S₂O₅); dithionic acid(H₂S₂O₆); pyrosulfuric acid (H₂S₂O₇); peroxydisulfuric acid (H₂S₂O₅);trithionic acid (H₂S₃O₆); tetrathionic acid (H₂S₄O₆); pentathionic acid(H₂S₅O₆); chiorosulfonic acid (HSO₃Cl); furosulfonic acid (HSO₃F);sulfamic acid (HSO₃NH₂); salts thereof; and the like.

Generally, the sulfur-containing inorganic acid salt may be an alkalimetal salt or an alkaline earth metal salt. For example, the salt may bea monovalent or divalent cation selected from Li⁺, Na⁺, K⁺, Rb⁺, Cs⁺,Fr⁺, Be²⁺, Mg²⁺, Ca²⁺, Sr²⁺, Ba²⁺, or Ra²⁺. Preferably, the salt isselected from the group consisting of Li⁺, Na⁺, K⁺, Mg²⁺, Ca²⁺, andcombinations thereof.

Alternatively, the sulfur-containing inorganic acid salt may be anammonium salt (NH₄ ⁺) or a quaternary ammonium salt. For example, thesulfur-containing inorganic acid salt may be a tetraalkylated ammoniumsalt; that is, a quaternary ammonium salt substituted with four alkylgroups preferably having from 1 to about 18 carbon atoms. Suitabletetraalkylated ammonium salts include, for example, tetramethylammoniumsalts, tetraethylammonium salts, tetrapropylammonium salts,tetrabutylammonium salts, and the like.

In one particular embodiment, the sulfur-containing inorganic acid isdithionous acid (H₂S₂O₄) or salts thereof. By way of example, salts ofdithionous acid include MHS₂O₄ and M₂S₂O₄, wherein M is selected fromalkali metal salts, alkaline earth metal salts, ammonium salt (NH₄ ⁺),and quaternary ammonium salts. According to this embodiment, theα,β-unsaturated ketone compound is chemically reduced to form themorphinan-6-one compound upon treatment with the sulfur-containingcompound, discussed in further detail below.

In another particular embodiment, the sulfur-containing inorganic acidis selected from the group consisting of sulfurous acid (H₂SO₃);disulfurous acid (H₂S₂O₅); and salts thereof. By way of example, saltsof sulfurous acid and disulfurous acid include MHSO₃, M₂SO₃, MHS₂O₅, andM₂S₂O₅ wherein M is selected from alkali metal salts, alkaline earthmetal salts, ammonium salt (NH₄ ⁺), and quaternary ammonium salts.According to this embodiment, the sulfur-containing inorganic acid orsalt thereof is one which dissociates into the bisulfite ion (HSO₃ ⁻)and/or the sulfite ion (SO₃ ²⁻) in the reaction mixture. It will beunderstood by one of ordinary skill in the art that sulfurous acid(H₂SO₃) generally exists as a solution of SO₂ (commonly about 6%) inwater. The pKa of sulfurous acid (H₂SO₃) is about 1.78 and itsionization expression is:

H₂O+SO₂↔H₂SO₃↔H⁺+HSO₃ ⁻↔H⁺+SO₃ ²⁻

According to this embodiment, various 1,2- and 1,4-sulfonated additionproducts are formed from the morphinan-6-one compound and theα,β-unsaturated ketone compound by reaction with the bisulfite ionand/or the sulfite ion, discussed in further detail below.

In another particular embodiment, the sulfur-containing compound is athiol having the formula: R—SH, wherein R is hydrocarbyl, substitutedhydrocarbyl, or heterocyclo. For example, R may be substituted orunsubstituted alkyl, alkenyl, alkynyl, or aryl. Exemplary thiols havingthe formula R—SH, wherein R is defined as above, include alkyl or arylthiols such as methanethiol, ethanethiol, benzenethiol, and the like.Other exemplary thiols include thiocarboxylic acids and salts thereof(e.g., thiobenzoic acid) and thiol-terminated carboxylic acids and saltsthereof (e.g., thioglycolic acid (mercaptoacetic acid),mercaptopropionic acid, and the like). Still other exemplary thiolsinclude amino acids (e.g., L- or D,L-cysteine), other thiol-containingamines and/or quaternary salts thereof (e.g., cysteamine HCl,thiocholine, and the like), or polymer-bound thiols (e.g., polycysteine,polyvinylarylthiol, and the like). In one preferred embodiment, thethiol is benzenethiol. Without being bound to one theory, it is believedthat the thiol forms various 1,2- and 1,4-sulfonated addition productsfrom the morphinan-6-one compound and the α,β-unsaturated ketonecompound.

The amount of sulfur-containing compound utilized to treat the reactionmixture may vary considerably according to the various reaction mixturecomponents (such as the particular morphinan-6-one compound, theα,β-unsaturated ketone compound, and/or the media material) andconcentrations thereof, time of reaction, temperature, pressure, and thelike. Relatively high usage rates of sulfur-containing compoundgenerally offer no significant advantages and tend to waste chemicalsand/or reactor volume.

The molar ratio of sulfur-containing compound to morphinan-6-onecompound in the reaction mixture is typically greater than about 0.5:1.Preferably, the molar ratio of sulfur-containing compound tomorphinan-6-one compound in the reaction mixture is from about 0.5:1 toabout 3.0:1. For example, the molar ratio of sulfur-containing compoundto morphinan-6-one compound in the reaction mixture may be from about0.5:1 to about 0.8:1, from about 0.5:1 to about 1.0:1, from about 0.5:1to about 1.5:1, from about 0.5:1 to about 2.0:1, or from about 0.5:1 toabout 2.5:1. More preferably, the molar ratio of sulfur-containingcompound to morphinan-6-one compound in the reaction mixture is fromabout 0.6:1 to about 2.8:1. For example, the molar ratio ofsulfur-containing compound to morphinan-6-one compound in the reactionmixture may be from about 0.6:1 to about 0.8:1, from about 0.6:1 toabout 1.0:1, from about 0.6:1 to about 1.5:1, from about 0.6:1 to about2.0:1, or from about 0.6:1 to about 2.5:1. Most preferably, the molarratio of sulfur-containing compound to morphinan-6-one compound in thereaction mixture is from about 0.8:1 to about 2.5:1. For example, themolar ratio of sulfur-containing compound to morphinan-6-one compound inthe reaction mixture may be from about 0.8:1 to about 1.0:1, from about0.8:1 to about 1.2:1, from about 0.8:1 to about 1.4:1, from about 0.8:1to about 1.6:1, from about 0.8:1 to about 1.8:1, from about 0.8:1 toabout 2.0:1, from about 0.8:1 to about 2.2:1, or from about 0.8:1 toabout 2.4:1.

The treatment of the reaction mixture with the sulfur-containingcompound may be carried out in ambient air or in an oxygen-freeenvironment. Preferably, the treatment is carried out in an inertatmosphere such as, for example, argon or nitrogen gas. The treatment ispreferably carried out at a pressure of from about 0.5 atm to about 2.0atm. More preferably, the treatment is carried out at a pressure of fromabout 0.75 atm to about 1.5 atm; most preferably from about 0.9 atm toabout 1.25 atm.

In various embodiments, the pH of the reaction mixture during treatmentwith the sulfur-containing compound is greater than about 3. Typically,the pH of the reaction mixture during treatment is less than about 10,although the upper pH limit may depend on the treatment time and/orsolubility of the various reaction mixture components. Preferably, thepH of the reaction mixture during treatment with the sulfur-containingcompound is from about 3 to about 9; more preferably from about 6 toabout 9. For example, the pH of the reaction mixture during treatmentwith the sulfur-containing compound may be about 3, about 4, about 5,about 6, about 7, about 8, or about 9. Most preferably, the treatmentoccurs at a pH of from about 6 to about 7.25. Upon the addition of thesulfur-containing compound to the reaction mixture including themorphinan-6-one compound and the α,β-unsaturated ketone compound, the pHmay be adjusted to the desired level (e.g. using a base such as ammoniumhydroxide). Other suitable bases include, for example, sodium hydroxide,potassium hydroxide, and the like.

The time of reaction is generally a function of the other variables inthe reaction, such as pH, ratio of media material to morphinan-6-onecompound, amount of sulfur-containing compound, and the like. Typically,some reduction of the concentration of α,β-unsaturated ketone compoundin the reaction mixture can be observed after about 1 hour. Preferably,the reaction mixture is treated with the sulfur-containing compound forat least about 1 hour. In some embodiments, the time of reaction is lessthan about 24 hours. In other embodiments, the time of reaction is fromabout 1 hour to about 18 hours; in still other embodiments from about 1hour to about 15 hours; in still other embodiments from about 1 hour toabout 10 hours. More preferably, the reaction mixture is treated withthe sulfur-containing compound for about 1 hour to about 5 hours. Forexample, the reaction mixture may be treated with the sulfur-containingcompound for about 1 hour, for about 2 hours, for about 3 hours, forabout 4 hours, or for about 5 hours.

The temperature of the reaction mixture during treatment with thesulfur-containing compound is generally from about 0° C. to about 100°C. For example, the temperature of the reaction mixture during treatmentwith the sulfur-containing compound may be from about 10° C. to about90° C., from about 20° C. to about 80° C., or from about 30° C. to about70° C. Preferably, the temperature of the reaction mixture duringtreatment with the sulfur-containing compound is above room temperature.The preferred reaction temperature may vary for each morphinan-6-one.More preferably, the temperature of the reaction mixture duringtreatment with the sulfur-containing compound is from about 30° C. toabout 50° C. For example, the temperature of the reaction mixture duringtreatment with the sulfur-containing compound may be about 30° C., about35° C., about 40° C., about 45° C., or about 50° C.

Once the treatment is complete or has proceeded as long as desired, thetreated morphinan-6-one compound is recovered to produce themorphinan-6-one product. Advantageously, the morphinan-6-one compoundmay be recovered from the reaction mixture without the use of an organicsolvent. The absence of the need for organic solvents in the recoveryprocess not only provides various environmental and material handlingbenefits, but also results in a more efficient process suitable forindustrial scale applications. Typically, the morphinan-6-one compoundis precipitated from the reaction mixture as a base (or salt ifdesirable) and may then be readily converted into a generally morepharmaceutically acceptable form, if so desired. For example, the pH ofthe reaction mixture is typically adjusted to about 9-10 or greater witha suitable base such as ammonium hydroxide, and the (desired)precipitated compound recovered. Generally speaking, this pH is at thepoint wherein opium alkaloids are not ionized. The morphinan-6-onecompounds can then be optionally converted into a form morephysiologically tolerable, such as the hydrochloride salt, e.g.,oxycodone HCl, using conventional methods known to those of skill in theart. For example, the morphinan-6-one base can be dissolved or otherwisedispersed in water, reacted with an acid such as HCl, heated, and cooledto precipitate the morphinan-6-one salt. By way of an alternativeexample, the morphinan-6-one base can be dissolved or otherwisedispersed in an alcohol solvent (e.g., methanol, ethanol, etc.) or asolvent system (i.e., a mixture of solvents), reacted with concentratedHCl or an HCl/alcohol mixture, and cooled to precipitate themorphinan-6-one hydrochloride salt. By way of another example, themorphinan-6-one base can be dissolved or otherwise dispersed in water,alcohol solvent, or a solvent system, reacted with gaseous HCl, heated,and cooled to precipitate the morphinan-6-one hydrochloride salt.

Treatment Reaction Mechanisms

Without being bound to one theory, it is believed that the reduction ofthe concentration of α,β-unsaturated ketone compounds in the reactionmixture is performed via different mechanisms, depending on theparticular sulfur-containing compound selected to treat the reactionmixture.

In one embodiment, the α,β-unsaturated ketone compound is reduced by thesulfur-containing compound to form the desired α,β-saturatedmorphinan-6-one compound. See, e.g., Camps et al., Tetrahedron Letters,Vol. 29, No. 45, 1988, 5811-5814; Louis-Andre et al., TetrahedronLetters, Vol. 26, No. 7, 1985, 831-832). By way of example, dithionousacid (H₂S₂O₄) and salts thereof (e.g., MHS₂O₄ or M₂S₂O₄, wherein M isdefined as above) operate according to this mechanism; othersulfur-containing compounds, however, may also operate according to thesame or a similar mechanism. Reaction Scheme 11 generally illustratesthe reduction of the α,β-unsaturated ketone compound (3) to form thedesired morphinan-6-one compound (2) according to this embodiment,wherein X, R₁, R₂, R₃, R₁₀, and R₁₄ are defined as above.

In an alternative embodiment, various 1,2- and 1,4-sulfonated additionproducts are formed during treatment that assist in the removal of theα,β-unsaturated ketone compounds from the reaction mixture. As notedabove, several sulfur-containing compounds dissociate into varioussulfur-containing species. In particular, sulfurous acid (H₂SO₃),disulfurous acid (H₂S₂O₅), and their salts dissociate into, among otherthings, bisulfite (HSO₃ ⁻) and sulfite (SO₃ ²⁻).

Bisulfite has been shown to add via radical initiation across isolateddouble bonds (see, e.g., March, J., Advanced Organic Chemistry, p. 688,J. Wiley & Sons, 1985, 3d. ed.) and/or add via an ionic mechanism (see,e.g., Gilbert, E.; Sulfonation and Related Reactions, p. 152,Interscience, N.Y. 1965; Patai et al, The Chemistry of Alkenes, p. 478,Interscience, London 1965). Without being bound to one theory, it isbelieved that when the reaction mixture is treated with sulfurous acid,disulfurous acid, or salts thereof and the pH is adjusted to betweenabout 3 and about 9, certain 1,2- and 1,4-addition products and adductsare stably and/or reversibly formed from the α,β-unsaturated ketonecompound and the morphinan-6-one compound. It is further believed thatthe products are generally stable within the pH range of from about 3 toabout 9, and adjusting the pH outside of this range after theirformation from the α,β-unsaturated ketone compounds and themorphinan-6-one compounds facilitates the removal of the α,β-unsaturatedketone compound from the reaction mixture, resulting in a highly puremorphinan-6-one product.

One preferred embodiment of the present invention is illustrated inReaction Schemes 12A and 12B, wherein X, R₁, R₂, R₃, R₁₀, and R₁₄ aredefined as above and M is a monovalent or divalent cation. For example,M may be one or more alkali metal or alkaline earth metal monovalent ordivalent cations from the sulfur-containing compound. Alternatively, Mmay be one or more monovalent or divalent cations from the alkalinecompound (e.g., NaOH, KOH, NH₄OH, etc.) used to adjust the pH of thereaction mixture to between about 3 and about 9 after the addition ofthe sulfur-containing compound to the reaction mixture.

As shown in Reaction Schemes 12A and 12B, various 1,2- and1,4-sulfonated compounds are formed from the morphinan-6-one compound(2) (scheme 12A) and the α,β-unsaturated ketone compound (3) (scheme12B) upon treatment of a reaction mixture including these compounds witha sulfur-containing compound at a pH of between about 3 and about 9.While it is understood that sulfurous acid, disulfurous acid, and saltsthereof operate according to the mechanism illustrated in ReactionSchemes 12A, 12B, and 12C, other sulfur-containing compounds may alsooperate according to the same or a similar mechanism. For example,thiols (e.g., benzenethiol) may also operate according to the mechanismdescribed in connection with Reaction Schemes 12A, 12B, and 12C.

Particularly, when the reaction mixture is treated with asulfur-containing compound and the pH of the reaction mixture isadjusted to between about 3 and about 9, the morphinan-6-one compound(2) forms the reversible, water-soluble 1,2-bisulfite adduct (2A). Oncethe reaction mixture is sufficiently in solution in the media materialand/or the sulfur-containing compound, dissociated sulfur specie (suchas sulfite and bisulfite) react more readily with the α,β-unsaturatedketone compound (3) also present in the reaction mixture.

As illustrated in Reaction Scheme 12B, one reaction between theα,β-unsaturated ketone compound (3) and the sulfur-containing compoundinvolves the rapid and reversible 1,2-addition of the bisulfite to thecarbonyl (similar to the reaction of the sulfur-containing compound withthe morphinan-6-one compound illustrated in Reaction Scheme 12A) to formthe reversible 1,2-adduct (3A) from the α,β-unsaturated ketone compound(3). Another reaction between the sulfur-containing compound and theα,β-unsaturated ketone compound (3) is the slower 1,4-addition, formingthe more stable 1,4-addition product (3B). The introduction of thesulfonate group in the β-position generally enhances the reactivity ofthe carbonyl group by destroying its conjugation with the double bond,such that the reversible product is a 1,2- and 1,4-bis adduct (3C) (seePatai et al., The Chemistry of Alkenes, p. 478, Interscience, London1965).

Reaction Scheme 12C illustrates the removal of certain addition productsformed in the reaction mixture according to Reaction Schemes 12A and 12Band the resulting highly pure morphinan-6-one product, wherein X, R₁,R₂, R₃, R₁₀, R₁₄, and M are defined as above.

As illustrated in Reaction Scheme 12C, the removal of theα,β-unsaturated ketone addition products is generally based in thedifferences in solubility of the 1,4-addition product (3B) generatedfrom the α,β-unsaturated ketone compound and the desired morphinan-6-onecompound (2). Adjusting the pH outside of the range between about 3 andabout 9 (i.e., the pH is adjusted to less than about 3 or the pH isadjusted to greater than about 9) with an acid (e.g., sulfuric acid(H₂SO₄)) or a base (e.g., ammonium hydroxide (NH₄OH)) results in thedecomposition of the 1,2-addition products of each compound, renderingthe desired morphinan-6-one compound (2) insoluble in water. Therelatively more stable 1,4-addition product (3B) formed from theα,β-unsaturated ketone compound remains and is water-soluble in thefinal mixture at an alkaline pH (e.g., pH ˜9 or greater). The1,4-addition product (38) may thus be removed from the mixture with themother liquor, leaving the insoluble morphinan-6-one base (2). Thedesired morphinan-6-one base may then be converted into a morephysiologically-tolerable salt form, such as the hydrochloride salt,using methods known to those of skill in the art.

One particularly preferred embodiment of the present invention isillustrated in Reaction Schemes 13A and 13B, wherein M is defined asabove.

As shown in Reaction Schemes 13A and 13B, various sulfonated compoundsare formed from oxycodone (20) (scheme 13A) and the α,β-unsaturatedketone compound 14-hydroxycodeinone (30) (scheme 13B) upon treatment ofa reaction mixture including these compounds with a sulfur-containingcompound at a pH of between about 3 and about 9. As discussed above,while it is generally understood that sulfurous acid, disulfurous acid,and salts thereof operate according to the mechanism described inReaction Schemes 13A and 13B, other sulfur-containing compounds may alsooperate according to the same or a similar mechanism.

Particularly, when the reaction mixture is treated with asulfur-containing compound and the pH of the reaction mixture isadjusted to between about 3 and about 9, oxycodone (20) forms thereversible, water-soluble 1,2-bisulfite adduct (20A). Once the reactionmixture is sufficiently in solution in the media material and thesulfur-containing compound, dissociated sulfur specie (such as sulfiteand bisulfite) react more readily with the 14-hydroxycodeinone (30) alsopresent in the reaction mixture.

As illustrated in Reaction Scheme 13B, one reaction between14-hydroxycodeinone (30) and the sulfur-containing compound involves therapid and reversible 1,2-addition of the sulfite to the carbonyl(similar to the reaction of the sulfur-containing compound withoxycodone illustrated in Reaction Scheme 13A) to form the reversible1,2-adduct (30A) from 14-hydroxycodeinone. Another reaction between thesulfur-containing compound and 14-hydroxycodeinone (30) is the slower1,4-addition, forming the more stable 1,4-addition product (30B). Theintroduction of the sulfonate group in the n-position generally enhancesthe reactivity of the carbonyl group by destroying its conjugation withthe double bond, such that the reversible product is a 1,2- and 1,4-bisadduct (30C) (see Patai et al., The Chemistry of Alkenes, p. 478,Interscience, London 1965).

Reaction Scheme 13C illustrates the removal of certain addition productsformed in the reaction mixture according to Reaction Schemes 13A and 13Band the resulting highly pure oxycodone, wherein M is defined as above.

As illustrated in Reaction Scheme 13C, the removal of the14-hydroxycodeinone addition products is generally based on thedifferences in solubility of the 1,4-addition product (30B) generatedfrom 14-hydroxycodeinone and the desired oxycodone (20). Adjusting thepH outside of the range between about 3 and about 9 (i.e., the pH isadjusted to less than about 3 or greater than about 9) with an acid(e.g., sulfuric acid (H₂SO₄)) or a base (e.g., ammonium hydroxide(NH₄OH)) results in the decomposition of the 1,2-addition products ofeach compound, rendering the desired oxycodone (20) insoluble in water.The relatively more stable 1,4-addition product (30B) formed from14-hydroxycodeinone remains and is water soluble in the final mixture atan alkaline pH (e.g., pH ˜9 or greater). The 1,4-addition product (30B)may thus be removed from the mixture with the mother liquor, leaving theinsoluble oxycodone base (20). The oxycodone base may then be convertedinto a more physiologically-tolerable salt form, such as thehydrochloride salt, using methods known to those of skill in the art.

Removal of Residual Sulfur-Containing Species from the Reaction Mixture

Using the process described herein to reduce the concentration ofα,β-unsaturated ketone compounds from a reaction mixture by treating thereaction mixture with a sulfur-containing compound may result in theundesirable accumulation of residual sulfur-containing species (such assulfites and bisulfites) in the reaction mixture and/or finalmorphinan-6-one product. Accordingly, the residual sulfur-containingspecies may be optionally substantially removed from the reactionmixture following the treatment with the sulfur-containing compoundusing a variety of methods known to those of skill in the art.

As described above, in various embodiments 1,2- and 1,4-sulfonatedaddition products may be formed by the reaction of a sulfur-containingcompound with the morphinan-6-one compound and the α,β-unsaturatedketone compound at a pH of between about 3 to about 9. The adjustment ofthe pH outside of this range eliminates the 1,2-addition products,renders the morphinan-6-one compound insoluble in water, and theremaining water soluble 1,4-addition product can be removed in the wastestream.

To optionally substantially remove the residual sulfur-containingspecies upon completion of the reaction with the sulfur-containingcompound, the pH of the reaction mixture may be adjusted to less thanabout 3 (instead of adjusting the pH to greater than 9) with an acid(e.g., sulfuric acid (H₂SO₄)) and manipulated prior to the precipitationof the morph inan-6-one compound as described in detail above. Morepreferably, the pH is adjusted to less than about 2. The reduction in pHconverts any residual sulfur species that may be present in the reactionmixture into SO₂ gas, which typically has a limited solubility in water.In one embodiment, the SO₂ gas may then be optionally heat refluxed outof the reaction mixture by conventional means known to those of skill inthe art. Typically, the reaction mixture is heat refluxed for about 2hours to about 5 hours. The temperature and pressure during reflux arealso generally variable. For example, the temperature of the reactionmixture during reflux is typically from about 20° C. to about 100° C.,and the reflux may be performed at a pressure of from about 0.003 atm toabout 1.0 atm. Alternatively, substantially all of the water (and theSO₂ gas) may be optionally distilled off to a receiver tank anddiscarded. This procedure is also generally known to those of skill inthe art.

As discussed above, after treatment of the reaction mixture with thesulfur-containing compound to reduce the concentration of theα,β-unsaturated ketone compound in the reaction mixture, themorphinan-6-one compound is recovered to produce the desiredmorphinan-6-one product. Generally speaking, recovery refers to one ormore of the precipitation, filtration and drying of the morphinan-6-onebase, the formation of the physiologically acceptable morphinan-6-onesalt (e.g., the hydrochloride salt), the removal of the residualsulfur-containing species, and/or combinations thereof, to produce amorphinan-6-one product.

The treatment of the reaction mixture with a sulfur-containing compoundaccording to the various processes and embodiments described hereinsignificantly reduces the concentration of α,β-unsaturated ketonecompounds in the reaction mixture, and a highly pure morphinan-6-oneproduct may be produced therefrom. Typically, the morphinan-6-oneproduct comprises less than about 0.1% (by weight morphinan-6-oneproduct) of an α,β-unsaturated ketone compound. For example, themorphinan-6-one product may comprise less than about 0.05% (by weightmorphinan-6-one product) of an α,β-unsaturated ketone compoundPreferably, the morphinan-6-one product comprises less than about 0.01%(by weight morphinan-6-one product) of an α,β-unsaturated ketonecompound. For example, the morphinan-6-one product may comprise lessthan about 0.005% (by weight morphinan-6-one product) of anα,β-unsaturated ketone compound. More preferably, the morphinan-6-oneproduct comprises less than about 0.001% (by weight morphinan-6-oneproduct) of an α,β-unsaturated ketone compound. For example, themorphinan-6-one product may comprise less than about 0.0005% (by weightmorphinan-6-one product) of an α,β-unsaturated ketone compound. Stillmore preferably, no detectable amount of an α,β-unsaturated ketonecompound is present in the morphinan-6-one product.

Abbreviations and Definitions

The following definitions and methods are provided to better define thepresent invention and to guide those of ordinary skill in the art in thepractice of the present invention. Unless otherwise noted, terms are tobe understood according to conventional usage by those of ordinary skillin the relevant art.

The term “alkyl” as used herein describes groups which are preferablylower alkyl containing from one to eight carbon atoms in the principalchain and up to 20 carbon atoms. They may be straight or branched chainor cyclic and include methyl, ethyl, propyl, isopropyl, allyl, benzyl,hexyl and the like.

The term “alkenyl” as used herein describes groups which are preferablylower alkenyl containing from two to eight carbon atoms in the principalchain and up to 20 carbon atoms. They may be straight or branched chainor cyclic and include ethenyl, propenyl, isopropenyl, butenyl,isobutenyl, hexenyl, and the like.

The term “alkynyl” as used herein describes groups which are preferablylower alkynyl containing from two to eight carbon atoms in the principalchain and up to 20 carbon atoms. They may be straight or branched chainand include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and thelike.

The term “aromatic” as used herein alone or as part of another groupdenotes optionally substituted homo- or heterocyclic aromatic groups.These aromatic groups are preferably monocyclic, bicyclic, or tricyclicgroups containing from 6 to 14 atoms in the ring portion. The term“aromatic” encompasses the “aryl” and “heteroaryl” groups defined below.

The term “aryl” as used herein alone or as part of another group denoteoptionally substituted homocyclic aromatic groups, preferably monocyclicor bicyclic groups containing from 6 to 12 carbons in the ring portion,such as phenyl, biphenyl, naphthyl, substituted phenyl, substitutedbiphenyl or substituted naphthyl. Phenyl and substituted phenyl are themore preferred aryl.

The terms “halogen,” “halide” or “halo” as used herein alone or as partof another group refer to chlorine, bromine, fluorine, and iodine.

The term “heteroatom” shall mean atoms other than carbon and hydrogen.

The terms “heterocyclo” or “heterocyclic” as used herein alone or aspart of another group denote optionally substituted, fully saturated orunsaturated, monocyclic or bicyclic, aromatic or non-aromatic groupshaving at least one heteroatom in at least one ring, and preferably 5 or6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygenatoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to theremainder of the molecule through a carbon or heteroatom. Exemplaryheterocyclo groups include heteroaromatics such as furyl, pyridyl,oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like.Exemplary substituents include one or more of the following groups:hydrocarbyl, substituted hydrocarbyl, hydroxy, protected hydroxy, acyl,acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino,cyano, ketals, acetals, esters and ethers.

The term “heteroaromatic” as used herein alone or as part of anothergroup denote optionally substituted aromatic groups having at least oneheteroatom in at least one ring, and preferably 5 or 6 atoms in eachring. The heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may bebonded to the remainder of the molecule through a carbon or heteroatom.Exemplary heteroaromatics include furyl, thienyl, pyridyl, oxazolyl,pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like. Exemplarysubstituents include one or more of the following groups: hydrocarbyl,substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl,acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino,nitro, cyano, thiol, ketals, acetals, esters and ethers.

The term “acyl,” as used herein alone or as part of another group,denotes the moiety formed by removal of the hydroxy group from the group—COOH of an organic carboxylic acid, e.g., RC(O)—, wherein R is R¹,R¹O—, R¹R²N—, or R¹S—, R¹ is hydrocarbyl, heterosubstituted hydrocarbyl,or heterocyclo, and R² is hydrogen, hydrocarbyl or substitutedhydrocarbyl.

The term “acyloxy,” as used herein alone or as part of another group,denotes an acyl group as described above bonded through an oxygenlinkage (—O—), e.g., RC(O)O— wherein R is as defined in connection withthe term “acyl.”

The term “heteroaryl” as used herein alone or as part of another groupdenote optionally substituted aromatic groups having at least oneheteroatom in at least one ring, and preferably 5 or 6 atoms in eachring. The heteroaryl group preferably has 1 or 2 oxygen atoms and/or 1to 4 nitrogen atoms in the ring, and is bonded to the remainder of themolecule through a carbon. Exemplary heteroaryls include furyl,benzofuryl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl,benzoxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl,indolizinyl, benzimidazolyl, indazolyl, benzotriazolyl,tetrazolopyridazinyl, carbazolyl, purinyl, quinolinyl, isoquinolinyl,imidazopyridyl and the like. Exemplary substituents include one or moreof the following groups: hydrocarbyl, substituted hydrocarbyl, hydroxy,protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy,halogen, amido, amino, cyano, ketals, acetals, esters and ethers.

The terms “hydrocarbon” and “hydrocarbyl” as used herein describeorganic compounds or radicals consisting exclusively of the elementscarbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, andaryl moieties. These moieties also include alkyl, alkenyl, alkynyl, andaryl moieties substituted with other aliphatic or cyclic hydrocarbongroups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwiseindicated, these moieties preferably comprise 1 to 20 carbon atoms.

The “substituted hydrocarbyl” moieties described herein are hydrocarbylmoieties which are substituted with at least one atom other than carbon,including moieties in which a carbon chain atom is substituted with ahetero atom such as nitrogen, oxygen, silicon, phosphorous, boron,sulfur, or a halogen atom. These substituents include halogen,heterocyclo, alkoxy, alkenoxy, aryloxy, hydroxy, protected hydroxy,acyl, acyloxy, nitro, amino, amido, nitro, cyano, ketals, acetals,esters and ethers.

The term “hydroxy protecting group” refers to hydrocarbyl andsubstituted hydrocarbyl moieties which bond to an hydroxy oxygen atom ina molecule so as to protect that oxygen atom from further reactionduring synthesis. This protection allows reactions to occur selectivelyat another reaction site on the same molecule. Examples of hydroxyprotecting groups include, but are not limited to, ethers such asmethyl, t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trityl,methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetra hydropyranyl,tetrahydrothiopyranyl, and trialkylsilyl ethers such as trimethylsilylether, triethylsilyl ether, dimethylarylsilyl ether, triisopropylsilylether and t-butyldimethylsilyl ether; esters such as benzoyl, acetyl,phenylacetyl, formyl, mono-, di-, and trihaloacetyl such aschloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl; andcarbonates including but not limited to alkyl carbonates having from oneto six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl; isobutyl, and n-pentyl; alkyl carbonates having from one to sixcarbon atoms and substituted with one or more halogen atoms such as2,2,2-trichloroethoxymethyl and 2,2,2-trichloroethyl; alkenyl carbonateshaving from two to six carbon atoms such as vinyl and allyl; cycloalkylcarbonates have from three to six carbon atoms such as cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl; and phenyl or benzyl carbonatesoptionally substituted on the ring with one or more C₁₋₈ alkoxy, ornitro.

Having described the invention in detail, it will be apparent thatmodifications and variations are possible without departing the scope ofthe invention defined in the appended claims. Furthermore, it should beappreciated that all examples in the present disclosure are provided asnon-limiting examples.

Example 1

In this Example, an oxycodone HCl sample was treated with asulfur-containing compound according to the processes described herein.

To a 250 ml, 3 neck round bottom flask equipped with a mechanicalstirrer, N₂ inlet, and thermocouple for temperature control was added 10g of oxycodone HCl (0.028 moles; >0.3% by weight 14-hydroxycodeinone(14-OHC) impurity). Next, with mixing 100 g of deoxygenated water (10minute N₂ purge) was added. The solution pH was adjusted to about 6 withammonium hydroxide. Next, 5.0 g of sodium dithionite (Na₂S₂O₄) wasadded. The pH was then adjusted to about 7 with concentrated ammoniumhydroxide. The resulting mixture was stirred at 70° C. for about 16hours.

After about 16 hours, the pH was adjusted to about 9 with ammoniumhydroxide, precipitating the oxycodone base. The mixture was stirred forabout 1 hour, and the precipitated oxycodone base was filtered, washedwith water, and dried overnight at 40° C. under reduced pressure.

The oxycodone base sample was converted to the oxycodone HCl salt bydissolving about 14.5 g of the oxycodone base in a 100 ml, 3 neck roundbottom flask equipped with a mechanical stirrer, N₂ inlet, andthermocouple for temperature control. Next, with mixing about 29 g ofH₂O and about 12.6 g of concentrated HCl was added. The resultingmixture was heated to about 65° C.-75° C. until substantially all was insolution. The heat was then removed, resulting in the precipitation ofthe oxycodone HCl salt. The precipitated mixture was stirred for about1-3 hours at less than about 10° C. and filtered to collect theprecipitated oxycodone HCl.

The 14-hydroxycodeinone (14-OHC) content was analyzed in the oxycodonebase sample and the oxycodone HCl sample using an Agilent HPLC with MSinterface capability. The results are illustrated in Table 1.

TABLE 1 Initial 14- Final 14-OHC content OHC content Oxycodone base (%Oxycodone HCl (% by wt.) by wt.) (% by wt.) 0.3 0.0005 0.0005

Examples 2A-2G

In Examples 2A-2G, an oxycodone HCl sample was treated with asulfur-containing compound according to the processes described herein.The treatment was performed at various temperatures, times of reaction,concentration of reactants, and pH.

Example 2A

To a 100 ml, 3 neck round bottom flask equipped with a mechanicalstirrer, N₂ inlet, and thermocouple for temperature control was added9.2 g of wet oxycodone HCl (0.02 moles; 0.13% by weight14-hydroxycodeinone (14-OHC) impurity). Next, with mixing 36.2 g of H₂Oand 40.3 g of 6 wt. % SO₂/H₂O solution was added. The resulting mixturewas heated to about 30° C. and the solution pH was adjusted to about 6with ammonium hydroxide. The mixture was stirred for about 3 hours. ThepH of the mixture was then adjusted to about 8.8-9.8 with concentratedammonium hydroxide and stirred for about 30 minutes. The precipitatedoxycodone base was then filtered from the mother liquor, washed withabout 25.73 g of H₂O, and dried. The 14-hydroxycodeinone content(14-OHC) in the oxycodone base was then measured as described in thepreceding Example.

The experiment was repeated using identical reagents, amounts thereof,and conditions to form the oxycodone base sample. This oxycodone basesample was converted to the oxycodone HCl salt as described in thepreceding example. The 14-hydroxycodeinone content (14-OHC) in theoxycodone base sample and the oxycodone HCl sample were then measured.

Results and reaction conditions for this experiment are illustrated inTable 2.

TABLE 2 Concentration Molar Ratio Initial 14- Final 14-OHC contentTemperature Time (g H₂O per g of SO₂ to OHC content Oxycodone OxycodoneTrial (° C.) (hr.) pH Oxycodone HCl) Oxycodone HCl (% by wt.) base (% bywt.) HCl (% by wt.) 1 30 3 6 10.2 1.8:1 0.13 0.0007 Not tested 2 30 3 610.2 1.8:1 0.13 0.0007 0.0007

Example 2B

This Example was performed according to the process described in Example2A. However, in this Example 9.4 g of wet oxycodone HCl (0.02 moles;0.13% by weight 14-hydroxycodeinone (14-OHC) impurity) was mixed withabout 34.6 g of H₂O and about 27.4 g of 6 wt. % SO₂/H₂O solution. Themixture was heated to about 50° C. Next, the pH was adjusted to about 7using ammonium hydroxide.

The resulting mixture was allowed to react for either 1 hour or 5 hours.At the end of the desired reaction time, the solution was adjusted to apH of 8.8-9.8 with about 2.0 g of concentrated ammonium hydroxide andstirred for about 30 minutes. The solids were filtered and washed withabout 28.0 g of H₂O and dried. The 14-hydroxycodeinone (14-OHC) contentin the resulting oxycodone base was measured, as was the14-hydroxycodeinone (14-OHC) content in the oxycodone HCl salt formedaccording to the method described in the preceding example. The resultsand reaction conditions in the various trials are illustrated in Table3.

TABLE 3 Concentration Molar Ratio Initial 14- Final 14-OHC contentTemperature Time (g H₂O per g of SO₂ to OHC content Oxycodone OxycodoneTrial (° C.) (hr.) pH Oxycodone HCl) Oxycodone HCl (% by wt.) base (% bywt.) HCl (% by wt.) 3 50 1 7 8.2 1.2:1 0.13 None detected None detected4 50 5 7 8.2 1.2:1 0.13 0.00005 0.0005

Example 2C

This Example was performed according to the process described in Example2A. However, in this Example 9.1 g of wet oxycodone HCl (0.02 moles;0.13-0.14% by weight 14-hydroxycodeinone (14-OHC) impurity) was mixedwith about 7.0 g of H₂O and about 52.8 g of 6 wt. % SO₂/H₂O solution.The mixture was heated to either 10° C. or 50° C. Next, the pH wasadjusted to 7 using ammonium hydroxide.

The resulting mixture was allowed to react for either 1 hour or 5 hours.At the end of the desired reaction time, the solution was adjusted to apH of 8.8-9.8 with about 2.0-2.5 g of concentrated ammonium hydroxideand stirred for about 30 minutes. The solids were filtered and washedwith about 28.0 g of H₂O and dried. The 14-hydroxycodeinone (14-OHC)content in the resulting oxycodone base was measured, as was the14-hydroxycodeinone (14-OHC) content in the oxycodone HCl salt formed bythe method described in the preceding example. The results and reactionconditions in the various trials are illustrated in Table 4.

TABLE 4 Concentration Molar Ratio Initial 14- Final 14-OHC contentTemperature Time (g H₂O per g of SO₂ to OHC content Oxycodone OxycodoneTrial (° C.) (hr.) pH Oxycodone HCl) Oxycodone HCl (% by wt.) base (% bywt.) HCl (% by wt.) 5 50 1 7 8.2 2.4:1 0.13 None detected 0.0006 6 50 57 8.2 2.4:1 0.13 0.00015 0.0004 7 10 5 7 8.2 2.4:1 0.14 0.001 Not tested

Example 2D

This Example was performed according to the process described in Example2A. However, in this Example 9.52 g of wet oxycodone HCl (0.02 moles;0.13% by weight 14-hydroxycodeinone (14-OHC) impurity) was mixed withabout 72.24 g of H₂O and about 27.76 g of 6 wt. % SO₂/H₂O solution. Themixture was heated to about 50° C. Next, the pH was adjusted to about 7using ammonium hydroxide.

The resulting mixture was allowed to react for either 1 hour or 5 hours.At the end of the desired reaction time, the solution was adjusted to apH of 8.8-9.8 with about 2.0-2.5 g of concentrated ammonium hydroxideand stirred for about 30 minutes. The solids were filtered and washedwith about 28.0 g of H₂O and dried. The 14-hydroxycodeinone (14-OHC)content in the resulting oxycodone base was measured, as was the14-hydroxycodeinone (14-OHC) content in the oxycodone HCl salt formed bythe method described in the preceding example. The results and reactionconditions in the various trials are illustrated in Table 5.

TABLE 5 Concentration Molar Ratio Initial 14- Final 14-OHC contentTemperature Time (g H₂O per g of SO₂ to OHC content Oxycodone OxycodoneTrial (° C.) (hr.) pH Oxycodone HCl) Oxycodone HCl (% by wt.) base (% bywt.) HCl (% by wt.) 8 50 1 7 13.1 1.2:1 0.13 0.0002 0.0003 9 50 5 7 13.11.2:1 0.13 None detected 0.0004

Example 2E

This Example was performed according to the process described in Example2A. However, in this Example 9.5 g of wet oxycodone HCl (0.02 moles;0.13-0.14% by weight 14-hydroxycodeinone (14-OHC) impurity) was mixedwith about 39.7 g of H₂O and about 55.6 g of 6 wt. % SO₂/H₂O solution.The mixture was heated to either 10° C. or 50° C. Next, the pH wasadjusted to about 7 using ammonium hydroxide.

The resulting mixture was allowed to react for either 1 hour or 5 hours.At the end of the desired reaction time, the solution was adjusted to apH of 8.8-9.8 with about 2.0-2.5 g of concentrated ammonium hydroxideand stirred for about 30 minutes. The solids were filtered and washedwith about 30.6 g of H₂O and dried. The 14-hydroxycodeinone (14-OHC)content in the resulting oxycodone base was measured, as was the14-hydroxycodeinone (14-OHC) content in the oxycodone HCl salt formed bythe method described in the preceding example. The results and reactionconditions in the various trials are illustrated in Table 6.

TABLE 6 Concentration Molar Ratio Initial 14- Final 14-OHC contentTemperature Time (g H₂O per g of SO₂ to OHC content Oxycodone OxycodoneTrial (° C.) (hr.) pH Oxycodone HCl) Oxycodone HCl (% by wt.) base (% bywt.) HCl (% by wt.) 10 50 1 7 12.3 2.4:1 0.13 None detected 0.0004 11 505 7 12.3 2.4:1 0.13 None detected 0.0004 12 10 5 7 12.3 2.4:1 0.130.0008 Not tested

Example 2F

To a 22 L, 3 neck round bottom flask equipped with a mechanical stirrer,N₂ inlet, and thermocouple for temperature control was added 1840 g ofwet oxycodone HCl (4.27 moles: 0.13% by weight 14-hydroxycodeinone(14-OHC) impurity). Next, with mixing 2706 g of H₂O and 7717 g of 6.4wt. % SO₂/H₂O solution was added. The resulting mixture was heated toabout 40° C. and the solution pH was adjusted to about 7 usingconcentrated ammonium hydroxide. The mixture was stirred for about 5hours.

After about 5 hours, the solution was adjusted to a pH of about 1.7 withthe addition of 293.0 g concentrated sulfuric acid (96-98%). Thepressure was slowly reduced to about 0.26 atm to facilitate thedistillation/removal of unreacted SO₂. As the distillation progressed,23.4 g of concentrated sulfuric acid was added as the pressure wasdecreased to about 0.11 atm and the solution temperature was increasedto about 50-55° C.

The solution was then cooled to about 30° C. and the solution pHadjusted to about 8.5-10 with concentrated ammonium hydroxide. Thesolution was stirred for about 30 minutes and filtered. The solids werefiltered and washed with about 2000 g of H₂O and dried. The14-hydroxycodeinone (14-OHC) content in the resulting oxycodone base wasmeasured, as was the 14-hydroxycodeinone (14-OHC) content in theoxycodone HCl salt formed by the method described in the precedingexample. The results and reaction conditions are illustrated in Table 7.

TABLE 7 Concentration Molar Ratio Initial 14- Final 14-OHC contentTemperature Time (g H₂O per g of SO₂ to OHC content Oxycodone OxycodoneTrial (° C.) (hr.) pH Oxycodone HCl) Oxycodone HCl (% by wt.) base (% bywt.) HCl (% by wt.) 13 40 5 7 6.6 1.8:1 0.13 0.0001 0.0005

Example 2G

To a 50 ml, 3 neck round bottom flask equipped with a mechanicalstirrer, N₂ inlet, and thermocouple for temperature control was added3.33 g of oxycodone HCl (0.0095 moles; 0.2% by weight14-hydroxycodeinone (14-OHC) impurity). Next, with mixing 33.3 g of H₂Oand 0.83 g of sodium bisulfite was added. The resulting mixture washeated to about 30° C. and the solution pH was adjusted to about 7 withammonium hydroxide. The mixture was stirred for about 15 hours. The pHof the mixture was then adjusted to about 8.8-9.8 with concentratedammonium hydroxide and stirred for about 60 minutes. The precipitatedoxycodone base was then filtered from the mother liquor, washed withabout 10.0 g of H₂O, and dried. The 14-hydroxycodeinone (14-OHC) contentin the resulting oxycodone base was measured, as was the14-hydroxycodeinone (14-OHC) content in the oxycodone HCl salt formed bythe method described in the preceding example. The results and reactionconditions in the various trials are illustrated in Table 8.

TABLE 8 Concentration Molar Ratio Initial 14- Final 14-OHC contentTemperature Time (g H₂O per g of SO₂ to OHC content Oxycodone OxycodoneTrial (° C.) (hr.) pH Oxycodone HCl) Oxycodone HCl (% by wt.) base (% bywt.) HCl (% by wt.) 14 30 15 7 10 0.84:1 0.2 0.0004 0.0004

Example 3

In this Example, an oxymorphone HCl sample was treated with asulfur-containing compound according to the processes described herein.

To a 250 ml, 3 neck round bottom flask equipped with a mechanicalstirrer, N₂ inlet, and thermocouple for temperature control was added150 g H₂O and 15 g oxymorphone HCl sample (0.044 moles; 0.3-0.5% byweight 14-hydroxymorphinone (14-OHM) impurity). Next, 7.5 g of sodiumbisulfite (NaHSO₃) was added. The pH was then adjusted to about 7 withconcentrated ammonium hydroxide, and the resulting mixture was stirredat 23° C. for about 16 hours.

After about 16 hours, the pH was adjusted to about 8.8-9.8 with ammoniumhydroxide and the solution was cooled to about 20° C. The precipitatedoxymorphone base was filtered, washed with water (about 45 g), and driedfor 4 hours at 65° C.

The oxymorphone base sample was analyzed using the methods describedabove, and the sample contained no detectable amount of14-hydroxymorphinone or 14-hydroxycodeinone. This experiment wasrepeated using a 6 wt. % SO₂/H₂O solution in place of sodium bisulfiteand similar results were obtained.

Example 4

In this Example, oxycodone base was treated with a thiol according tothe processes described herein.

To a 25 ml, 3 neck round bottom flask equipped with a mechanicalstirrer, N₂ inlet, and thermocouple for temperature control was added3.0 g oxycodone base (0.01 moles; 0.3-0.5% by weight 14-hydroxycodeinone(14-OHC) impurity). Next, 18 g of chloroform was added, and the mixturewas stirred at 70° C. until the oxycodone base was dissolved. After themixture was substantially homogenous, 1.5 g of benzenethiol was added tothe mixture with stirring.

After about 16 hours, a sample was analyzed using the methods describedin the preceding examples. HPLC area percent analysis indicated a14-hydroxycodeinone level of less than about 0.0022%.

1.-50. (canceled)
 51. A composition comprising oxymorphone andcontaining about 0.001% or less, by weight of said oxymorphone, of anα,β unsaturated ketone.
 52. The composition of claim 51 wherein said α,βunsaturated ketone is 14-hydroxymorphinone or 14-hydroxycodeinone. 53.The composition of claim 51 wherein said α,β unsaturated ketone is14-hydroxymorphinone.
 54. The composition of claim 51 wherein said α,βunsaturated ketone is 14-hydroxymorphinone or 14-hydroxycodeinone and no14-hydroxymorphinone or 14-hydroxycodeinone is detectable by highperformance liquid chromatography with mass spectrometry detection. 55.The composition of claim 51 wherein said α,β unsaturated ketone is14-hydroxymorphinone and said composition comprises about 0.0005% orless, by weight of said oxymorphone, of 14-hydroxymorphinone.
 56. Thecomposition of claim 51 wherein said α,β unsaturated ketone is14-hydroxymorphinone or 14-hydroxycodeinone and said compositioncomprises about 0.0005% or less, by weight of said oxymorphone, of14-hydroxymorphinone or 14-hydroxycodeinone.
 57. The composition ofclaim 51, wherein the oxymorphone is an oxymorphone salt.
 58. Thecomposition of claim 53, wherein the oxymorphone is an oxymorphone salt.59. The composition of claim 55, wherein the oxymorphone is anoxymorphone salt.
 60. The composition of claim 51, wherein theoxymorphone is oxymorphone HCl.
 61. The composition of claim 53, whereinthe oxymorphone is oxymorphone HCl.
 62. The composition of claim 55,wherein the oxymorphone is oxymorphone HCl.
 63. A pharmaceuticalformulation comprising oxymorphone and containing about 0.001% or less,by weight of said oxymorphone, of an α,β unsaturated ketone.
 64. Thepharmaceutical composition of claim 63 wherein said α,β unsaturatedketone is 14-hydroxymorphinone or 14-hydroxycodeinone.
 65. Thepharmaceutical composition of claim 63 wherein said α,β unsaturatedketone is 14-hydroxymorphinone.
 66. The pharmaceutical composition ofclaim 63 comprising about 0.0005% or less, by weight of saidoxymorphone, of an α,β unsaturated ketone.
 67. The pharmaceuticalcomposition of claim 63 comprising about 0.0005% or less, by weight ofsaid oxymorphone, of 14-hydroxymorphinone.
 68. The pharmaceuticalcomposition of claim 63 wherein said oxymorphone is oxymorphone HCl. 69.The pharmaceutical composition of claim 65 wherein said oxymorphone isoxymorphone HCl.
 70. The pharmaceutical composition of claim 67 whereinsaid oxymorphone is oxymorphone HCl.